This invention relates to benzothiophenes, particularly 2-hydroxybenzothiophenes having the unusual 3-enamido side chains, for example, ##STR1##
These novel compounds can be effective cyclooxygenase and 5-lipoxygenase inhibitors and therefore can be useful in the treatment of inflammation and other prostaglandins and/or leukotriene mediated diseases.
Among various potent biological mediators derived from the oxygenation of arachidonic acid, prostaglandins and leukotrienes have been linked to various diseases. Notably, the biosynthesis of prostaglandins has been identified as a cause of inflammation, arthritic conditions (e.g., rheumatoid arthritis, osteoarthritis and gout), psoriasis, inflammatory bowel disease, and pain. Furthermore, the formation of leukotrienes has been connected to immediate hypersensitivity reactions and proinflammatory effects. It has been established that arachidonic acid undergoes oxygenation via two major enzymatic pathways:
(1) The pathway catalyzed by the enzyme cyclooxygenase; and PA0 (2) The pathway catalyzed by the enzyme 5-lipoxygenase. PA0 R.sup.1, R.sup.2 and R.sup.3 independently are PA0 R.sup.4 is PA0 R is H or C.sub.1-6 alkanoyl; PA0 R.sup.2 and R.sup.3 independently are: PA0 R.sup.4 is H or --CH.dbd.CHR.sup.2. PA0 N-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-(2,2-diphenylethenyl)-2-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-3-ca rboxamide; PA0 N-(2,2-diphenylethenyl)-2-hydroxy-6-(trifluoromethyl)benzo[b]thiophene-3-ca rboxamide; PA0 N-(2,2-di-2-thienyl)-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-[2-phenyl-2-(2-thienyl)ethenyl]-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-[2-(2-furyl)-2-phenylethenyl]-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-methyl-N-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-(2,2-diphenylethenyl)-5-fluoro-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-cyano-2-hydroxybenzo[b]thiophene-3-car boxamide; PA0 N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-fluoro-2-hydroxy-6-methoxybenzo[b]thio phene-3-carboxamide; PA0 N-[2-phenyl-2-(p-methylthiophenyl)-ethenyl]-2-hydroxy-5-(trifluoromethyl)-b enzo[b]thiophene-3-carboxamide; PA0 N-[2-(p-methylthiophenyl)-2-(2-thienyl)-ethenyl]-2-hydroxybenzo[b]thiophene -3-carboxamide; PA0 N-(2,2-diphenylethenyl)-5-(difluoromethyl)-2-hydroxybenzo[b]thiophene-3-car boxamide; PA0 N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-(1,1-difluoroethyl)-2-hydroxybenzo[b]t hiophene-3-carboxamide; PA0 N-[2-(3-methyl-2-furyl)-2-phenylethenyl]-5-chloro-2-hydroxybenzo[b]thiophen e-3-carboxamide; PA0 N-(2,2-diphenylethenyl)-5-formyl-2-hydroxybenzo[b]thiophene-3-carboxamide; PA0 N-[2-(m-fluorophenyl)-2-phenylethenyl]-2-hydroxy-5-(methylthio)-benzo[b]thi ophene-3-carboxamide; PA0 N-[2-(o-fluorophenyl)-2-phenylethenyl]-2-hydroxy-5-(methylthio)-benzo[b]thi ophen-3-carboxamide; PA0 N-[2-phenyl-2-(2-thienyl)ethenyl]-2-hydroxy-5-(methylsulfinyl)-benzo[b]thio phene-3-carboxamide.
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Bailey et al. Ann. Rpts. Med. Chem., 17, 203 (1982)).
Through recent research, 5-lipoxygenase inhibitors has been linked to the treatment of eye inflammation and used as cytoprotective agents.
To be an effective and acceptable topical agent for treating eye inflammation, a drug must not only penetrate the ophthalmic tissues to reach the active sites within the eye, but it must also be devoid of those side effects including irritation, allergic reaction and the like which would militate against long term administration.
With respect to the cytoprotective activity, it has been known that (1) gastric cytoprotection does not involve inhibition of gastric acid secretion. For example, protaglandin F2B does not inhibit gastric acid secretion, but it does induce gastric cytoprotection (S. Szabo et al., Experimentia, 38, 254, 1982); (2) lower effective dosages of cytoprotective agents are required than that of gastric acid inhibitors; and (3) the cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of gastrointestinal mucosa to strong irritants. For example, animal studies have shown that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline, etc.